Process for preparing novel 7-thioester derivatives of 3H pyrrolo [1,2-a]-imidazole and 8-thioester derivatives of imidazo [1,2-a] pyridine

ABSTRACT

The instantly claimed invention is a process for preparing novel 7-thioether derivatives of 2-aryl, 3 aryl, and 2,3-diary-2,5,7,7-tetra-hydro-3H-pyrrolo [1,2-a] imidazole and 8-thio-ether derivatives of 2-aryl, 3-aryl, and 2,3-diaryl-2,3,5,7,7,8-hexahydro-imidazo [1,2-a]-pyridine which comprises (a) contacting the corresponding amidine with about one molar equivalent of R 1  SSR 1  in the presence of about two molar equivalents of base and at a temperature of -78° C. to about 0° C. (b) contacting the corresponding amidine compound with about two molar equivalents of R,SSR, in the presence of about two molar equivalents of a base and at a temperature of from about -78° C. to about 23° C., said compounds being useful as immunomodulators.

This application is a division of application Ser. No. 518,514 filedJuly 29, 1983 now U.S. Pat. No. 4,507,481.

BACKGROUND OF THE INVENTION

This invention relates to novel 2-aryl, 3-aryl, and2,3-diaryl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-a]imidazoles substituted inthe 7-position by a substituted ether or thioether group, to novel2-aryl, 3-aryl and2,3-diaryl-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridines substituted inthe 8-position by a substituted ether or thioether group, and to methodsfor the preparation of said imidazoles and pyridines.

The basic ring structures,2-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo-[1,2-a]imidazole and2-phenyl-2,3,5,6,7,8-hexahydro-3H-imidazo-[1,2-a]pyridine, have beendescribed in H. Mohrle et al, Arch. Pharmaz., 306(5), 325-338 (1973);and the basic ring structures,3-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-a]imidazole and3-phenyl-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine, have beendescribed in H. Mohrle et al, Z. Naturforsch, 31b, 99-105 (1976). Noneof the ring systems is associated with any interesting pharmacology andit is not believed that any ether or thioether derivatives have beenreported.

BRIEF SUMMARY OF THE INVENTION

The present invention pertains to new 2-aryl, 3-aryl, and2,3-diaryl-2,5,6,7-tetrahydro-7-(substituted oxo orthio)-3H-pyrrolo[1,2-a]imidazoles and 2-aryl, 3-aryl, and2,3-diaryl-2,3,5,6,7,8-hexahydro-8-(substituted oxo orthio)-imidazo[1,2-a]pyridines, including such compounds having adouble-bond at the 2,3-position, wherein the 7 position of theimidazoles and the 8 position of the pyridines are mono- ordi-substituted with --XR₁, where X is O or S(O)n; n is 0,1, or 2; and R₁is hydrogen, lower alkyl, phenyl, benzyl, or phenyl or benzylsubstituted with lower alkyl, amino, lower alkylamino, nitro, halogen(preferably chloro), hydroxy or lower alkoxy, including allstereoisomers, racemic and optically active forms, and including allpharmaceutically acceptable addition salts of these compounds. By theterm "lower alkyl" as used herein is intended an alkyl group, straightor branched, containing four or less carbon atoms.

DETAILED DESCRIPTION Utility

The compounds of this invention have been found to modulateimmunological functions in warm-blooded animals. Immunomodulators areused, for example, in the control of neoplastic diseases, infectiousdiseases including those of bacterial or viral origin, inflammatory andallergic reactions, autoimmune and immunodeficiency diseases.

Compounds

Preferred compounds are those of the formula ##STR1## where X and R₁ areas defined above; R₂ is H or XR₁ ; A is CH₂ or CH₂ CH₂ ; R₃ and R₄ areindependently selected from H, lower alkyl, aryl (preferably phenyl), oraryl substituted with lower alkyl, amino, lower alkylamino, nitro,hydroxy, lower alkoxy or halogen (preferably chloro), provided that atleast one of R₃ and R₄ is aryl or substituted aryl; and R₅ and R₆ areeach hydrogen or join to form a double bond at the 2,3-position.

Formation of Compounds

The thioether substituted amidine compounds can be prepared by thereaction of a disulfide (R₁ SSR₁) and the corresponding 2-aryl, 3-arylor 2,3-diaryl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-a]imidazole or 2-aryl,3-aryl or 2,3-diaryl-2,3,5,6,7,8-hexahydro-3H-imidazo[1,2-a]pyridinesubstrate in the presence of a suitable base such as n-butyl lithium.

The ratios of substrate, base, and disulfide are important for highyields of the desired mono- or disulfenylated compound. In general,optimal mono-sulfenylation is obtained with one equivalent of theamidine compound to one equivalent of disulfide to two equivalents ofbase. Additional disulfide increases the amount of disulfenylation andreduced amounts of base also result in increased disulfenylation as wellas unreacted starting material at the expense of monosulfenylatedproduct. The preferred reactant ratios for disulfenylation are oneequivalent of amidine to two equivalents of disulfide to two equivalentsof base.

The temperature range for monosulfenylation can be from about -78° C. toabout 0° C., preferably at or below -10° C. From 0° C. to 23° C.,disulfenylation becomes prominent. In disulfenylation, the lowertemperatures are still preferred, but up to about 23° C. can betolerated.

The preferred reaction solvent is tetrahydrofuran, although etherealsolvents and hydrocarbons such as diethyl ether, dioxane, n-hexane, andtoluene can also be employed. The reaction times are not critical andare dependent on the reactants, reactant ratios, temperature, and thelike. Such times normally range from about 0.5 to about 2.0 hours,although up to about 12 hours should not be detrimental.

Several different bases can be used, such as n-butyl lithium, lithiumdiisopropyl amide and sodium amide. Butyl lithium is used in thefollowing representative examples.

The sulfoxide compounds (wherein X is SO) can be prepared by oxidationof the corresponding thioethers (wherein X is S) with an organic peracidsuch as metachloroperbenzoic acid in methylene chloride.

The sulfone compounds (wherein X is SO₂) can be prepared by oxidation ofthe corresponding thioethers or their sulfoxide derivatives with excesspotassium hydrogen persulfate in methanol according to the generalprocedure of B. Trost and D. Curran, Tetrahedron Lett., 22, 1287(1981).

Ether derivatives (wherein X is O) can be prepared by reaction of thethioether derivatives with an excess of a positive halogenating agentsuch as chloramine-T in alcohol solvent or N-bromosuccinimide inmethanol-acetonitrile mixtures. The temperature employed for thisreaction is not critical. It should be high enough to provide areasonable rate but not so high as to cause decomposition. The boilingpoint of the reacting alcohol can conveniently be employed and can beexpected to provide a reasonable rate of reaction.

The pharmaceutically acceptable acid addition salts of the substitutedamidine compounds of this invention can be formed with strong ormoderately strong organic or inorganic acids by methods known to theart. For example, an ethanolic solution of the amidine may be treatedwith inorganic acid to give the desired amine salt as a solid. Exemplaryof the salts which are included in this invention are fumarate, maleate,citrate, lactate, oxalate, tartrate, hydrochloride, hydrobromide,sulfate, nitrate and phosphate salts.

The starting 2-aryl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-a]imidazoles and2-aryl-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridines can be prepared bythe procedure of H. Mohrle et al., Arch Pharmaz., 306(5), 325 (1973).The starting 3-aryl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-a]imidazoles and3-aryl-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridines can be prepared bythe procedure of H. Mohrle et al., Z. Naturforsch, 31b, 99 (1976).

Alternatively, the 3-aryl and the2,3-diaryl-2,5,6,7-tetrahydro-3H-pyrrolo-[1,2-a]imidazoles and the3-aryl and the 2,3-diaryl-2,3,5,6,7,8-hexahydroimidazo-[1,2-a]pyridinescan be prepared by reaction of cyclic methylthioimines as their acidaddition salts (such as 2-methylthio-3,4,5,6-tetrahydropyridiniumiodide) with 2-aryl and 2,3-diarylaziridines. The preferred reactionsolvent is alcohol although polar aprotic solvents such asdimethylformamide and dimethylsulfoxide can be employed as well.Reaction temperatures of 0° to 150° C. are suitable for the reactionwith the reflux temperature of solvent conveniently employed. Thereaction times are not critical and are dependent on the reactants,temperature, and the like. Such times normally range from 1 to 3 hours,although up to 24 hours has not been found to be deterimental. Thereaction has been found to behave regiospecifically such that when a2-arylaziridine is used, only the 3-aryl amidine derivatives are formed.Furthermore, when optically active 2-phenylaziridine is employed, onlyracemic amidine is recovered. The starting thioimines and aziridines aregenerally available in the literature.

General procedures used in the following representative examples forpreparation of the thioether compounds are as follows:

(A) Monosulfenylation of Amidines: n-Butyl lithium (2 equivalents) isadded in the presence of nitrogen to a stirred, cold (-78° C.) solutionof the amidine (1 equivalent) in dry THF (tetrahydrofuran). After 30-60minutes, the requisite disulfide (1 equivalent), dissolved or suspendedin THF, is added, and the reaction is allowed to stir for a further 1hour at -78° C. and is then allowed to warm to -10° C. over 1.5 hours.The mixture is poured onto cold 1 normal HCl, washed with ether toremove thiol by-product and any unreacted disulfide, neutralized withsaturated NaHCO₃ solution and extracted with solvents such as ether ortoluene to give the monosulfenylated amidines, usually as oils.Treatment of an ethanolic solution of the free base with ethanolic HClor ethanolic H₂ SO₄ gives the desired hydrochloride or sulfate salts assolids.

(B) Disulfenylation of Amidines: The procedure for preparation of thedisulfenylated amidine is the same as in General Procedure (A), exceptthat 2 equivalents of the requisite disulfide are added. Treatment of anethanolic solution of the free base with an inorganic acid gives thedesired amine salt as a solid.

In the following examples, all temperatures are in degrees centigrade.

ILLUSTRATIVE EXAMPLES Example 1 Preparation of2,5,6,7-Tetrahydro-2-phenyl-7-methylthio-3H-pyrrolo[1,2-a]imidazolehydrochloride

To a solution of 4.8 g (0.026 mol) of2,5,6,7-tetrahydro-2-phenyl-3H-pyrrolo[1,2-a]imidazole in 50 ml of dryTHF and stirred at -75° under N₂ was added dropwise 19.8 ml (0.052 mol)of n-BuLi (2.6M in n-hexane). The resulting dark-colored solution wasstirred at -75° for 1 hr and was then treated all at once with 2.4 g(0.026 mol) of dimethyl disulfide in 10 ml of THF. After stirring at-75° for 1 hr, the reaction mixture was allowed to warm to -10° (11/2hr), and the yellow-orange solution was then poured onto 250 ml ofice-cold 1N HCl solution. The colorless aqueous solution was washed withEt₂ O to remove thiol and was then neutralized with saturated NaHCO₃solution. The pale yellow mixture was extracted with Et₂ O (3×1 liter);the ethereal extracts were combined on the basis of TLC and evaporatedto afford 2.6 g (43.1%) of the monosulfenylated amidine free base as atan oil. Treatment of an ethanolic solution (5 ml) of themonosulfenylated amidine with EtOH/HCl and dilution with Et₂ O afforded1.35 g (19.3%) hydrochloride salt as a tan amorphous powder; m.p.189°-190°.

Anal. Calc'd for C₁₃ H₁₇ ClN₂ S: C, 58.08; H, 6.37; Cl, 13.18; N, 10.42;S, 11.92. Found: C, 57.91; H, 6.42; Cl, 13.88; N, 10.30; S, 11.35.

Example 2 Preparation of2,5,6,7-Tetrahydro-2-phenyl-7-phenyl-thio-3H-pyrrolo[1,2-a]imidazolehydrochloride

2,5,6,7-Tetrahydro-2-phenyl-3H-pyrrolo[1,2-a]imidazole was reacted with2 equivalents of n-BuLi and 1 equivalent of diphenyl disulfide accordingto the general procedure A above and afforded the free base as anamorphous solid in 84.6% yield. Treatment of an ethanolic solution ofthe free base with EtOH/HCl followed by Et₂ O yielded the hydrochloridesalt as an amorphous colorless powder (33.7%); m.p. 202°-204°.

Anal. Calc'd for C₁₈ H₁₉ ClN₂ S: C, 65.34; H, 5.78; Cl, 10.71; N, 8.46;S, 9.69. Found: C, 65.39; H, 5.84; Cl, 10.99; N, 8.46; S, 9.69.

Example 3 Preparation of2,5,6,7-Tetrahydro-2-phenyl-7-p-methoxybenzylthio-3H-pyrrolo[1,2-a]imidazolehydrochloride

2,5,6,7-Tetrahydro-2-phenyl-3H-pyrrolo[1,2-a]imidazole was reacted with2 equivalents of n-BuLi and 1 equivalent of p-methoxybenzyl disulfideaccording to the general procedure A above and afforded the free base asa dark green oil in 62% yield. Treatment of an ethanolic solution of thefree base with EtOH/HCl followed by Et₂ O yielded the hydrochloride saltas a cream-colored amorphous powder (27.9%); m.p. 195°-197°.

Anal. Calc'd for C₂₀ H₂₃ ClN₂ OS: C, 64.07; H, 6.18; Cl, 9.45; N, 7.47;O, 4.26; S, 8.55. Found: C, 64.02; H, 6.21; Cl, 9.27; N, 7.46; O, 4.47;S, 9.18.

Example 4 Preparation of2,5,6,7-Tetrahydro-2-phenyl-7,7-di(methylthio)-3H-pyrrolo[1,2-a]imidazoleperchlorate

2,5,6,7-Tetrahydro-2-phenyl-3H-pyrrolo[1,2-a]imidazole was reacted with2 equivalents of n-BuLi and 2 equivalents of dimethyl disulfideaccording to the general procedure B and afforded the disulfenylatedamidine free base as an oil in 69.3% yield. Treatment of an ethanolicsolution of the amidine free base with HClO₄ yielded the solidperchlorate salt (45.8%); m.p. 181°-183°.

Anal. Calc'd for C₁₄ H₁₉ ClN₂ O₄ S₂ : C, 44.38; H, 5.05; Cl, 9.36; N,7.39; O, 16.89 Found: C, 44.48; H, 5.18; Cl, 9.56; N, 7.23; O, 16.85.

Example 5 Preparation of2,5,6,7-Tetrahydro-2-phenyl-7,7-di(phenylthio)-3H-pyrrolo[1,2-a]imidazole

2,5,6,7-Tetrahydro-2-phenyl-3H-pyrrolo[1,2-a]imidazole was reacted with2 equivalents of n-BuLi and 2 equivalents of diphenyl disulfideaccording to the general procedure B and afforded the disulfenylatedamidine free base as a colorless solid (62.2%); m.p. 154°-156°.

Anal. Calc'd for C₂₄ H₂₂ N₂ S₂ : C, 71.60; H, 5.50; N, 6.95; S, 15.92.Found: C, 71.42; H, 5.67; N, 6.83; S, 15.76.

Example 6 Preparation of2,5,6,7-Tetrahydro-2-phenyl-7-i-propylthio-3H-pyrrolo[1,2-a]imidazolehydrochloride

2,5,6,7-Tetrahydro-2-phenyl-3H-pyrrolo[1,2-a]imidazole was reacted with2 equivalents of n-BuLi and 1 equivalent of i-propyldisulfide accordingto the general procedure A above and afforded the free base as a yellowoil in 79.8% yield. Treatment of an ethanolic solution of the free basewith EtOH/HCl followed by Et₂ O yielded the hydrochloride salt as anamorphous colorless powder (9.3%); m.p. 240°-242°.

Anal. Calc'd for C₁₅ H₂₁ ClN₂ S: C, 60.68; H, 7.13; Cl, 11.94; N, 9.43;S, 10.80 Found: C, 60.57; H, 7.13; Cl, 12.40; N, 9.42; S, 11.11.

Example 7 Preparation of2,5,6,7-Tetrahydro-2-phenyl-7-n-butylthio-3H-pyrrolo[1,2-a]imidazolehydrochloride

2,5,6,7-Tetrahydro-2-phenyl-3H-pyrrolo[1,2-a]imidazole was reacted with2 equivalents of n-BuLi and 1 equivalent of n-butyldisulfide accordingto the general procedure A above and afforded the free base as a darkoil in 50% yield. Treatment of an ethanolic solution of the free basewith EtOH/HCl followed by Et₂ O yielded the hydrochloride salt as anamorphous grey solid (8.9%); m.p. 223°-225°.

Anal. Calc'd for C₁₆ H₂₃ ClN₂ S: C, 61.82; H, 7.46; Cl, 11.40; N, 9.01;S, 10.31 Found: C, 61.85; H, 7.77; Cl, 11.80; N, 9.03; S, 10.57.

Example 8 Preparation of2,5,6,7-Tetrahydro-2-p-methoxyphenyl-7-phenylthio-3H-pyrrolo[1,2-a]imidazolehydrochloride

2,5,6,7-Tetrahydro-2-p-methoxyphenyl-3H-pyrrolo[1,2-a]imidazole wasreacted with 2 equivalents of n-BuLi and 1 equivalent ofdiphenyldisulfide according to the general procedure A above andafforded the free base as a colorless solid in 78.5% yield; m.p.115°-119°. Treatment of an ethanolic solution of the free base withEtOH/HCl followed by Et₂ O yielded the hydrochloride salt as anamorphous colorless powder (20.1%); m.p. 230°-232°.

Anal. Calc'd for C₁₉ H₂₁ ClN₂ OS: C, 63.23; H, 5.86; Cl, 9.82; N, 7.76;S, 8.88 Found: C, 62.48; H, 5.77; Cl, 9.94; N, 7.40; S, 8.85.

Example 9 Preparation of2,5,6,7-Tetrahydro-2-phenyl-7-(2,6-dichlorophenylthio)-3H-pyrrolo[1,2-a]imidazolehydrochloride

2,5,6,7-Tetrahydro-2-phenyl-3H-pyrrolo[1,2-a]imidazole was reacted with2 equivalents of n-BuLi and 1 equivalent of 2,6-dichlorophenyldisulfideaccording to the general procedure A above except that when the reactionmixture was poured into the aq HCl solution, the HCl salt of the desiredproduct precipitated. It was collected, washed well with cold H₂ O, thenEt₂ O and dried in vacuo; yield 40.7%; m.p. 96°-99°. Neutralization ofthe acidic filtrate with NaHCO₃, followed by extraction with Et₂ O,yielded an additional amount of the desired product as the free base(39.2%).

Anal. Calc'd. for C₁₈ H₁₇ Cl₃ N₂ S: C, 50.96; H, 4.30; Cl, 24.78; N,6.48; S, 7.98 Found: C, 50.93; H, 4.66; Cl, 25.31; N, 6.60; S, 7.55

Example 10 Preparation of2,3,5,6,7,8-Hexahydro-2-phenyl-8-methylthioimidazo[1,2-a]pyridinehydrochloride

To a solution of 10.2 g (0.051 mol) of2,3,5,6,7,8-hexahydro-2-phenylimidazo[1,2-a]pyridine in 100 ml of dryTHF and stirred at -75° under N₂ was added dropwise 41.5 ml (0.102 mol)of n-BuLi (2.45M in n-hexane). The resulting blood-red solution wasstirred at -75° for 50 min and was then treated all at once with 4.8 g(0.051 mol of dimethyl disulfide in 20 ml of dry THF. After stirring at-75° for 1 hr, the reaction mixture was allowed to warm to -10° (˜11/2hr) and the yellow-orange solution was then poured onto 500 ml ofice-cold 1N HCl solution. The colorless aqueous solution was washed withEt₂ O (3×500 ml) to remove thiol and was then neutralized with saturatedNaHCO₃ solution. The pale yellow mixture was extracted with Et₂ O (6×500ml), toluene (4×500 ml) and, finally, CHCl₃ (1×500 ml). The organicextracts were combined on the basis of TLC (CHCl₃ :EtOH:NH₄OH(25%)40:60:2); thus, Et₂ O extracts 2-6 and toluene extracts 1-4 werecombined, dried and evaporated to afford 6.5 g (51.7%) of areddish-brown oil identified by NMR as the monosulfenylated product;evaporation of Et₂ O extract 1 afforded 300 mg of a mixture of mono- anddisulfenylated product; evaporation of CHCl₃ extract afforded 900 mg ofa mixture of monosulfenylated product and starting material in a ratioof 1:10.

Further basification of the original bicarbonate solution with 2.5N NaOHsolution and extraction with CHCl₃ gave 2.5 g of unreacted amidine uponevaporation of the CHCl₃ extracts.

Dissolution of the monosulfenylated amidine product in 5 ml of absoluteEtOH, acidification with EtOH/HCl and dilution with Et₂ O afforded 3.3 g(22.9%) of the hydrochloride salt as a colorless, amorphous solid; m.p.176°-178°.

Anal. Calc'd for C₁₄ H₁₉ ClN₂ S: C, 59.45; H, 6.77; Cl, 12.53; N, 9.90;S, 11.33 Found: C, 59.54; H, 6.73; Cl, 13.08; N, 9.89; S, 11.07

Example 11 Preparation of2,3,5,6,7,8-Hexahydro-2-phenyl-8-phenylthioimidazo[1,2-a]pyridinesulfate (1:1) salt

2,3,5,6,7,8-Hexahydro-2-phenylimidazo[1,2-a]pyridine was reacted with 2equivalents of n-BuLi and 1 equivalent of diphenyl disulfide accordingto the general procedure A above and afforded the free base as an oil in91.2% yield. Treatment of the free base with EtOH/H₂ SO₄ followed by Et₂O afforded the monosulfate salt as an amorphous powder (47.8%); m.p.170°-175°.

Anal. Calc'd for C₁₉ H₂₂ N₂ O₄ S₂ C, 56.13; H, 5.45; N, 6.89; O, 15.74;S, 15.77 Found: C, 55.94; H, 5.50; N, 6.77; O, 15.99; S, 15.81

Example 12 Preparation of2,3,5,6,7,8-Hexahydro-2-phenyl-8-p-tolylthioimidazo[1,2-a]pyridinesulfate (1:1) salt

2,3,5,6,7,8-Hexahydro-2-phenylimidazo[1,2-a]pyridine was reacted with 2equivalents of n-BuLi and 1 equivalent of p-tolyldisulfide according tothe general procedure A above and afforded the free base as an oil in90.6% yield. Treatment of the free base with EtOH/H₂ SO₄ followed by Et₂O afforded the monosulfate salt as a colorless, amorphous powder(22.8%); m.p. 154°-156°.

Anal. Calc'd for C₂₀ H₂₄ N₂ O₄ S₂ : C, 56.00; H, 5.92; N, 6.47; O,17.07; S, 15.27 Found: C, 56.03; H, 5.85; N, 6.53; O, 16.65; S, 14.96

Example 13 Preparation of2,3,5,6,7,8-Hexahydro-2-phenyl-8-p-chlorophenylthioimidazo[1,2-a]pyridinesulfate (1:1) salt

2,3,5,6,7,8-Hexahydro-2-phenylimidazo[1,2-a]pyridine was reacted with 2equivalents of n-BuLi and 1 equivalent of bis(p-chlorophenyl)disulfideaccording to the general procedure A above and afforded the free base asan oil in 90.1% yield. Treatment of the free base with EtOH/H₂ SO₄followed by Et₂ O afforded the monosulfate salt as a colorless,amorphous powder (22.7%); m.p. 135°-139°.

Anal. Calc'd for C₁₉ H₂₁ Cl₁ N₂ O₄ S₂ : C, 51.75; H, 4.80; Cl, 8.03; N,6.35; O, 14.51; S, 14.54 Found: C, 51.82; H, 4.95; Cl, 7.91; N, 6.17; O,15.28; S, 14.57

Example 14 Preparation of2,3,5,6,7,8-Hexahydro-2-phenyl-8-benzylthiomidazo[1,2-a]pyridinefumarate (1:1) salt

2,3,5,6,7,8-Hexahydro-2-phenylimidazo[1,2-a]pyridine was reacted with 2equivalents of n-BuLi and 1 equivalent of benzyl disulfide according tothe general procedure A above and afforded the free base as an oil in56.5% yield. Treatment of the free base in n-propanol with 1 equivalentof fumaric acid followed by Et₂ O afforded the fumarate salt as acolorless, amorphous powder (32.5%); m.p. 124°-129°.

Anal. Calc'd for C₂₄ H₂₆ N₂ O₄ S: C, 65.73; H, 5.97; N, 6.38; O, 14.59;S, 7.31 Found: C, 65.83; H, 6.20; N, 6.63; O, 14.92; S, 7.00

Example 15 Preparation of2,3,5,6,7,8-Hexahydro-2-phenyl-8-p-methoxybenzylthioimidazo[1,2-a]pyridinefumarate (1:1) salt

2,3,5,6,7,8-Hexahydro-2-phenylimidazo[1,2a]pyridine was reacted with 2equivalents of n-BuLi and 1 equivalent of p-methoxybenzyl disulfideaccording to the general procedure A above and afforded the free base asan oil in 52.7% yield. Treatment of the free base in n-propanol with 1equivalent of fumaric acid followed by Et₂ O afforded the fumarate saltas an off-white, amorphous solid (39.7%); m.p. 147°-149°.

Anal. Calc'd for C₂₅ H₂₈ N₂ O₅ S: C, 64.08; H, 6.02; N, 5.97; O, 17.07;S, 6.84 Found: C, 63.58; H, 6.22; N, 5.98; O, 17.01; S, 6.81

Example 16 Preparation of2,3,5,6,7,8-Hexahydro-2-phenyl-8,8-di(methylthio)imidazo[1,2-a]pyridinehydrochloride

2,3,5,6,7,8-Hexahydro-2-phenylimidazo[1,2-a]pyridine was reacted with 2equivalents of n-BuLi and 2 equivalents of dimethyl disulfide accordingto general procedure B and afforded the free base as a solid in 90.2%yield; m.p. 87°-89°. Treatment of the free base with EtOH/HCl followedby ether yielded the hydrochloride salt as a colorless amorphous powderin 42.6% yield; m.p. 185°-188°.

Anal. Calc'd for C₁₅ H₂₁ ClN₂ S₂ : C, 54.77; H, 6.43; Cl, 10.77; N,8.51; S, 19.49 Found: C, 54.90; H, 6.42; Cl, 10.85; N, 8.54; S, 19.21

Example 17 Preparation of2,3,5,6,7,8-Hexahydro-2-phenyl-8,8-di(phenylthio)imidazo[1,2-a]pyridinefumarate

2,3,5,6,7,8-Hexahydro-2-phenylimidazo[1,2-a]pyridine was reacted with 2equivalents of n-BuLi and 2 equivalents of diphenyl disulfide accordingto the general procedure B and afforded the free base as an oil in 81.9%yield. Treatment of the free base in n-propanol with an equivalent offumaric acid followed by ether afforded the fumarate salt as anoff-white amorphous solid (52); m.p. 157°-159°.

Anal. Calc'd for C₂₉ H₂₈ N₂ O₄ S₂ : C, 65.39; H, 5.29; N, 5.25; O,12.01; S, 12.03 Found: C, 65.13; H, 5.21; N, 5.21; O, 12.46; S, 11.89

Example 18 Preparation of2,3,5,6,7,8-Hexahydro-2-phenyl-8-i-propylthioimidazo[1,2-a]pyridinesulfate

2,3,5,6,7,8-Hexahydro-2-phenylimidazo[1,2-a]pyridine was reacted with 2equivalents of n-BuLi and 1 equivalent of isopropyldisulfide accordingto the general procedure A above and afforded the free base as a solidin 52.1% yield. Treatment of the free base with EtOH/H₂ SO₄ followed byEt₂ O afforded the monosulfate salt as a light tan amorphous powder(20.2%); m.p. 116°-119°.

Anal. Calc'd for C₁₆ H₂₄ N₂ S₂ O₄ : C, 51.59; H, 6.49; N, 7.52; S,17.21; O, 17.18. Found: C, 51.27; H, 6.52; N, 7.47; S, 17.10; O, 17.10.

Example 19 Preparation of2,3,5,6,7,8-Hexahydro-2-phenyl-8-methylthioimidazo[1,2-a]pyridinefumarate (1:1) salt

2,3,5,6,7,8-Hexahydro-2-phenylimidazo[1,2-a]pyridine was reacted with 2equivalents of n-BuLi and 1 equivalent of dimethyldisulfide according tothe general procedure A above and afforded the free base as areddish-brown oil. Treatment of the free base in n-propanol with 1equivalent of fumaric acid followed by Et₂ O afforded the fumarate saltas an off-white, amorphous solid (53.1%); m.p. 160°-161°.

Anal. Calc'd for C₁₈ H₂₂ N₂ O₄ S: C, 59.64; H, 6.11; N, 7.72; O, 17.65;S, 8.84. Found: C, 59.60; H, 6.23; N, 7.57; O, 17.69; S, 8.80

Example 20 Preparation of2,3,5,6,7,8-Hexahydro-2-phenyl-8-(2,6-dichlorophenylthio)imidazo[1,2-a]pyridinehydrochloride

2,3,5,6,7,8-Hexahydro-2-phenylimidazo[1,2-a]pyridine was reacted with 2equivalents of n-BuLi and 1 equivalent of 2,6-dichlorophenyldisulfideaccording to the general procedure A above and afforded the free base asa colorless oil in 94.6% yield. Treatment of the free base with EtOH/HClfollowed by Et₂ O afforded the monohydrochloride salt as a colorlessamorphous powder (23.7%); m.p. 193°-196°.

Anal. Calc'd for C₁₉ H₁₉ Cl₃ N₂ S: C, 55.15; H, 4.62; Cl, 25.70; N,6.76; S, 7.74 Found: C, 54.97; H, 4.79; Cl, 24.78; N, 6.92; S, 8.02

Example 21 Preparation of2,3,5,6,7,8-Hexahydro-3-phenyl-8-phenylthioimidazo[1,2-a]pyridinesulfate

2,3,5,6,7,8-Hexahydro-3-phenylimidazo[1,2-a]pyridine was reacted with 2equivalents of n-BuLi and 1 equivalent of diphenyldisulfide according tothe general procedure A above and afforded the free base as a reddishoil in 95.2% yield. Treatment of an ethanol solution of the free basewith EtOH/H₂ SO₄ followed by Et₂ O afforded the sulfate salt as anoff-white powder (35.4%); mp 118°-120°.

Example 22 Preparation ofcis-2,3-Diphenyl-2,3,5,6,7,8-Hexahydro-8-phenylthioimidazo[1,2-a]pyridine

cis-2,3-Diphenyl-2,3,5,6,7,8-hexahydroimidazo[1,2a]pyridine was allowedto react with 2 equivalents of n-BuLi and 1 equivalent ofdiphenyldisulfide according to the general procedure A and afforded thefree base as an oil in 68% yield.

Example 23 Preparation of2,3,5,6,7,8-Hexahydro-2-phenyl-8,8-dimethoxyimidazo[1,2-a]pyridinehydrochloride

To a solution of2,3,5,6,7,8-hexahydro-2-phenyl-8-phenylthioimidazo[1,2-a]pyridine (30gm, 0.1 mol) dissolved in 740 ml of MeOH was added Chloramine-T (89 gm,0.3 mol) in 740 ml of MeOH and the solution was heated at reflux underN₂ for 16 hrs. The solution was then allowed to cool to room temperatureand the solvent was evaporated off at reduced pressure. The oily residuewas taken up in CHCl₃, washed with 2.5N NaOH, dried (Na₂ SO₄) andfiltered. The filtrate was extracted with dilute HCl, the acidicextracts combined, basified with aqueous NaHCO₃ solution and extractedwith 10% MeOH/CHCl₃. The organic extracts were combined, dried, andevaporated to afford 20 gm (81.3%) of the dimethyl ketal as a lightbrown oil. Treatment of an ethanol solution of the free base withEtOH/HCl followed by Et₂ O gave 12.5 gm (44.4%) of the hydrochloridesalt as a colorless amorphous powder; mp 186°-188°.

Anal. Cal'd for C₁₅ H₂₁ ClN₂ O₂ : C 60.70; H, 71.3; Cl, 11.95; N, 9.44Found: C, 60.54; H, 71.4; Cl, 11.90; N, 9.34

Example 24 Preparation of2,3,5,6,7,8-Hexahydro-2-phenyl-8,8-diethoxyimidazo[1,2-a]pyridinesulfate

Reaction of2,3,5,6,7,8-hexahydro-2-phenyl-8-phenylthioimidazo[1,2-a]pyridine withChloramine-T as in the above example but using EtOH in place of MeOHafforded the diethoxy ketal as a dark oil. Treatment of an ethanolsolution of the free base with EtOH/H₂ SO₄ followed by Et₂ O yielded thesulfate salt as a colorless amorphous powder; mp 142°-144°.

Anal. Calc'd for C₁₇ H₂₆ N₂ O₆ S: C, 52.83; H, 6.78; N, 7.25; S, 8.30Found: C, 52.45; H, 6.77; N, 7.23; S, 8.61

Example 25 Preparation of2,5,6,7-Tetrahyro-2-phenyl-7,7-dimethoxy-3H-pyrrolo[1,2-a]imidazolesulfate

To a methanol solution (135 ml) of2,5,6,7-tetrahydro-2-phenyl-7,7-diphenylthio-3H-pyrrolo[1,2-a]imidazole(5.35 g) under N₂ was added, all at once, Chloramine-T (15.2 g)suspended in MeOH (135 ml) and the bright yellow solution was heated atreflux for 16 hrs. The solution was then allowed to cool to roomtemperature and the solvent was evaporated off at reduced pressure. Theoily residue was taken up in CHCl₃, washed with 2.5N NaOH, dried (Na₂SO₄) and filtered. The filtrate was extracted with dilute HCl. Theacidic extracts were combined, basified with aqueous NaHCO₃ solution andextracted with 10% MeOH/CHCl₃. The organic extracts were combined,dried, and evaporated to afford 3.0 gm (91.6%) of the dimethyl ketal asa viscous oil. Treatment of an ethanol solution of the free base withEtOH/H₂ SO₄ followed by Et₂ O gave the sulfate salt as an amorphouspowder (33.9%); mp 146°-148°.

Anal. Calc'd for C₁₄ H₂₀ N₂ O₆ S: C, 49.40; H, 6.16; N, 7.92; S, 9.44Found: C, 48.49; H, 5.95; N, 7.88; S, 9.44

Example 26 Preparation of 2,3,5,6,7,8-Hexahydro-3-phenyl-8,8-dimethoxyimidazo[1,2-a]pyridine hydrochloride

To a solution of2,3,5,6,7,8-hexahydro-3-phenyl-8-phenylthioimidazo[1,2-a]pyridine (13.7g, 0.046 mol) dissolved in 350 ml of MeOH was added Chloramine-T (39.7g, 0.14 mol) in 350 ml of MeOH and the solution was heated at refluxunder N₂ for 16 hrs. The solution was allowed to cool to roomtemperature and the solvent was evaporated off at reduced pressure. Theoily residue was taken up in CHCl₃, washed with 2.5N NaOH, dried (Na₂SO₄) and filtered. The filtrate was extracted with dilute HCl, theacidic extracts combined, basified with aqueous NaHCO₃ solution andextracted with 10% MeOH/CHCl₃. The organic extracts were combined,dried, and evaporated to afford 7.2 g (60.2%) of the dimethyl ketal as abrown oil. Treatment of an ethanol solution of the free base withEtOH/HCl followed by Et₂ O afforded 3.5 g (25.7%) of the hydrochloridesalt as a colorless amorphous powder; mp 183°-185°.

Anal. Calc'd for C₁₅ H₂₁ ClN₂ O₂ : C, 60.70; H, 71.3; Cl, 11.95; N 9.44Found: C, 60.38; H, 7.18; Cl, 12.14; N, 9.30

Example 27 Preparation ofcis-2,3-Diphenyl-2,3,5,6,7,8-hexahydro-8,8-dimethoxyimidazo[1,2-a]pyridinesulfate

Treatment ofcis-2,3-diphenyl-2,3,5,6,7,8-hexahydro-8-phenylthioimidazo[1,2-a]pyridinewith Chloramine-T and MeOH as described in Example 26 afforded thedimethyl ketal as an orange oil. Treatment of an ethanol solution of thefree base with EtOH/H₂ SO₄ followed by Et₂ O gave the sulfate salt as anoff-white powder; mp 139°-140°.

Example 28 Preparation of2,3,5,6,7,8-Hexahydro-2-phenyl-8-phenylsulfinylimidazo[1,2-a]pyridinesulfate

To 9.65 g (0.032 mol) of2,3,5,6,7,8-hexahydro-2-phenyl-8-phenylthioimidazo[1,2-a]pyridinedissolved in 500 ml of CH₂ Cl₂ and cooled in an ice bath to 0° was addedportionwise 7.1 g of m-chloroperbenzoic acid. After 3 hrs. at 0°, thesolution was washed with aqueous NaHCO₃ solution, dried and evaporated.The residual semi-solid was dissolved in EtOH, treated with EtOH/H₂ SO₄followed by Et₂ O yielding the sulfoxide (41%) as a colorless amorphouspowder; mp 121°-123°.

Anal. Calc'd for C₁₉ H₂₂ N₂ O₅ S₂ : C, 54.01; H, 5.25; N, 6.63; S, 15.18Found: C, 53.84; H, 5.39; N, 6.53; S, 14.69

Example 29 Preparation of2,3,5,6,7,8-Hexahydro-2-phenylsulfonylimidazo[1,2-a]pyridine sulfate

To 3.0 g (9 mmoles) of2,3,5,6,7,8-hexahydro-2-phenyl-8-phenylthioimidazo[1,2-a]pyridinedissolved in 50 ml of MeOH and cooled in an ice bath to 0° was added asolution of potassium hydrogen persulfate (16.6 g) in 50 ml of H₂ O.After the addition, the mixture was allowed to warm to room temperatureand stir for 4 hours. Water (100 ml) was then added and the mixture wasextracted with CHCl₃ (3×50 ml). The CHCl₃ extracts were combined, dried(Na₂ SO₄) and evaporated to afford the sulfone as a yellowish oil in 92%yield. Treatment of an ethanol solution of the free base with EtOH/H₂SO₄ gave 1.5 g (38.1%) of the sulfate salt as a colorless amorphoussolid; mp 211°-213°.

Anal. Calc'd for C₁₉ H₂₂ N₂ O₆ S₂ : C, 52.04; H, 5.06; N, 6.38; S, 14.62Found: C, 51.60; H, 5.19; N, 6.37; S, 14.74

Example 30 Preparation of5,6,7,8-Tetrahydro-2-phenyl-8-phenylthioimidazo[1,2-a]pyridine sulfate

5,6,7,8-Tetrahydro-2-phenylimidazo[1,2-a]pyridine was allowed to reactwith 2 equivalents of n-BuLi and 1 equivalent of diphenyl disulfideaccording to the general procedure A and afforded the monosulfenylatedfree base as an oil in 65% yield. Treatment of an ethanol solution ofthe free base with EtOH/H₂ SO₄ gave the sulfate salt as a colorlessamorphous solid (35.2%); mp 214°-217°.

Anal. Calc'd for C₁₉ H₂₀ N₂ O₄ S₂ : C, 56.42; H, 4.99; N, 6.93; S, 15.85Found: C, 56.44; H, 5.23; N, 6.70; S, 15.60

Example 31 Preparation of2,3,5,6,7,8-Hexahydro-3-phenyl-imidazo[1,2a]pyridine--By The AziridineMethod

To 0.5 g (4.1 mol) of 2-phenylaziridine dissolved in 15 ml of MeOh wasadded 1.0 g (3.9 mmol) of 2-methylthio-3,4,5,6-tetrahydropyridiniumiodide and the resulting yellow reaction mixture was heated at refluxunder N₂ for 2 hours. The reaction mixture was then allowed to cool toRT, the solvent evaporated off, and the residual oil taken up in CH₂Cl₂. The CH₂ Cl₂ solution was washed with N NaOH, dried and evaporatedto afford 0.9 g (100%) of the 3-phenylamidine derivative as a colorlessoil; nmr and tlc were identical with material prepared by the method ofMohrle (Z. Naturforsch, 31b, 99-105; 1976).

Example 32 Preparation ofcis-2,3-Diphenyl-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine--AziridineMethod

Treatment of cis-2,3-diphenylaziridine with2-methylthio-3,4,5,6-tetrahydropyridinium iodide as in Example 31afforded the cis-2,3-diphenylamidine derivative as a colorless solid; mp115°-117°.

Anal. Calc'd for C₁₉ H₂₀ N₂ : C, 82.57; H, 7.29; N, 10.14 Found: C,82.13; H, 7.25; N, 10.10

Example 33 Preparation of5,6,7,8-Tetrahydro-2-phenyl-8,8-diphenylthioimidazo[1,2-a]pyridine

5,6,7,8-Tetrahydro-2-phenylimidazo[1,2-a]pyridine was reacted with2-equivalents of n-BuLi and 2 equivalents of diphenyldisulfide accordingto the general procedure B above and afforded the free base as an oil.Crystallization from ethanol gave the free base as off-white crystals(52.9%); mp 129°-131°.

Anal. Calc'd for C₂₅ H₂₃ N₂ S₂.1/2H₂ O: C, 70.89; H, 5.47; N, 6.61; S,15.14 Found: C, 71.40; H, 5.49; N, 6.39; S, 14.28

Example 34 Preparation of2,3,5,6,7,8-Hexahydro-8,8-dimethoxy-4-methyl-2-phenylimidazo[1,2-a]pyridiniumiodide

To 3.5 g of2,3,5,6,7,8-hexahydro-8,8-dimethoxy-2-phenylimidazo[1,2-a]pyridinedissolved in 100 ml of acetone was added in rapid drops with stirring1.25 ml (excess) methyl iodide and the yellow solution was let standundisturbed for 16 hours. The solid precipitate which had deposited wasfiltered off, washed well with cold acetone and air-dried; yield ofcolorless needles 4.1 g (75.0%), mp 176°-178°.

Anal. Calc'd for C₁₆ H₂₃ N₂ O₂ I: C, 47.77; H, 5.76; N, 6.96; O, 7.95;I, 31.53 Found: I, 31.22

Example 35--Chemotaxis Assay

In this assay, done according to the methods of R. Synderman et al.,Infection & Immunity, 11, p. 488-492 (1975) and M. S. Meltzer et al., J.Natl. Cancer Inst., 54, p. 795-799 (1975), the ability of a drugsubstance to influence the movement of cells responding to a stimulusinduced by some foreign substance or injury is determined. The resultsare reported in Table 35. This in vitro assay utilizes achemoattractant, derived from a component of the immunological systemknown as complement, to induce murine macrophage cells to migrate towardit. The effect of a drug substance on such movements can be measured bycounting the cells. Inflammation is a result of massive cell migrationto the injured site and, thus, a compound exhibits anti-inflammatoryactivity by inhibiting cell migration. For example, the compound ofExample 1 inhibits migration by 68.2% at 10⁻¹⁰ molar concentration andis thus an immunosuppressant. Conversely, macrophages can destroy tumorsand, thus, compounds exhibit potential anti-cancer activity bystimulating migration of these cells. For example, the compound ofExample 15 stimulates migration by 35.6% at 10⁻⁸ molar concentration andis thus immunoenhancing.

                  TABLE 35                                                        ______________________________________                                        Compound of Percent Inhibition (-) or Enhancement (+)                         at Dose of:                                                                            10.sup.-5                                                                             10.sup.-7                                                                             10.sup.-8                                                                           10.sup.-9                                                                           10.sup.-10                                                                          10.sup.-11                         Example No:                                                                            m       m       m     m     m     m                                  ______________________________________                                         1       -25.4    -8.8   -17.5 -29.7 -68.2 -36.8                               3       -94.9   -64.5   -43.0 -29.2 --    --                                 10       -94.1   -94.4   -88.4 -91.7 -97.4 -97.3                              14       -29.1   -51.0   -51.0 -50.7 -10.2 -44.5                              15        +2.6   +30.1   +35.6 +31.8 +33.8  -1.2                              ______________________________________                                    

Example 36--Kennedy Plaque Assay

In this assay, in which the in vitro model used was the Kennedymodification of the Jerne (or plaque) technique (J. C. Kennedy et al,Immunol., 20, p. 253 (1971)), the animal's humoral immune system isdepressed artificially by the known immunosuppressant drug,6-mercaptopurine (6-MP), and then the ability of a drug to eithersuppress it further or restore it towards normal is evaluated. Theresults are reported in Table 36. The change in the number of plaques,which is a direct correlate of the change in the number of antibodysecreting cells in the spleen, is used to measure this effect. Forexample, the compound of Example 11 results in greater than 100%restoration of the number of plaques and thus causes animmunoenhancement of the humoral system. In contrast, the compound ofExample 28 results in about 24% further suppression of the number ofplaques and thus behaves as an immunosuppressant.

                  TABLE 36                                                        ______________________________________                                        Kennedy Plaque Assay                                                          Treatment with 60 mg/Kg                                                                          Percent Restoration (+)                                    of 6MP plus 6.25 mg/Kg (i.p.)                                                                    or Suppression (-)                                         of compound of example No.                                                                       (%)                                                        ______________________________________                                         1                 +72                                                         2                 +29                                                         3                 +108                                                        7                 -49                                                         .sup. 8.sup.1     .sup. -36.sup.2                                            10                 +55                                                        11                 +125                                                       12                 +50                                                        13                 +103                                                       15                 +54                                                        16                 -25                                                        .sup. 17.sup.1     .sup. -37.sup.2                                            18                 +97                                                        20                 -49                                                        23                 +64                                                        28                 -24                                                        33                 +25                                                        ______________________________________                                         .sup.1 without 6MP treatment                                                  .sup.2 percent change from control (i.e., without 6MP)                   

Example 37--Anti-inflammatory Assay

The anti-inflammatory properties of various compounds of this inventionwere determined by carrageenan-induced paw edemas of test rats. Male,Sprague-Dawley rats (Blue Spruce Farm) were ordered at 125-140 g, housedfor one week, and allowed food and water ad libitum. At the time of theexperiments, only rats weighing 160-200 g were used.

All compounds were dissolved or suspended in a 0.5% water solution ofMethocel and orally administered to groups of six rats each. Controlrats received Methocel only. Two hours later (unless otherwise stated),paw edema was induced by subcutaneous injection into the planar surfaceof the right hind paw of 0.1 ml of a 1.0% homogenized suspension ofcarrageenan.

Immediately, the volume of the paw was measured by immersing it inmercury to above the lateral mateolus. The mercury in a glass cylinder25 mm in diameter and 60 mm deep was connected at the bottom on thecylinder by a column of water to a Statham transducer (model P23BB),range 0-5 cm of mercury pressure. The volume was recorded electronicallyon a Beckman recorder, R511. Three hours later, the inflamed paw volumewas measured again, and the change in volume was recorded for eachgroup. The percent inhibition of edema was calculated using the controlgroup paw volume as 100% edema, i.e., as (the change in edema in thecontrol group less the change in edema in the test group) times 100divided by the change in edema in the control group. The results arereported in Table 37.

                  TABLE 37                                                        ______________________________________                                        Anti-inflammatory Assay                                                       Effect on Carrageenan Induced Edema                                           Example      Dose (p.o.)                                                                             Percent                                                No.          mg/Kg     Inhibition (%)                                         ______________________________________                                        17           50        38.6                                                   18           50        40.4                                                   20           100       33.3; 39.6                                             23           50        -3.2                                                   .sup. 23.sup.1                                                                             50        34.5, 49.5                                             .sup. 23.sup.2                                                                             50        32.1                                                   ______________________________________                                         .sup.1 16 hrs. predosed                                                       .sup.2 20 hrs. predosed                                                  

Example 38--Antiviral Assay--Hepatitis In Mice

Female mice weighing approximately 21-24 grams were inoculated with 0.1ml of a mouse liver suspension containing mouse hepatitis virus, whichliver suspension is at a dilution of 10⁻⁵.5. Starting twenty-four hourspost-virus inoculation, the animals were intraperitoneally ("i.p.") ororally administered the test compound(s) once daily for 3 days. On day4, one third to one half of each group of mice were sacrificed and theirliver removed for examination. Each liver was scored and assigned anumber from 0 (normal liver) to 4 (extreme discoloration). The meanliver score per group was computed. The number of animals survivinguntil termination of the study (day 21) was also recorded. The resultsare reported in Table 38. Anti-hepatitis activity is evidenced byincreased survivor numbers and improved liver scores.

                  TABLE 38                                                        ______________________________________                                        Antiviral Activity Against Hepatitis in Mice                                  Example                                                                              Dose (i.p.) Percent Survival                                                                           Mean                                          No.    mg/Kg       %            Liver Score                                   ______________________________________                                        control                                                                              --          5            2.6                                           16      6.25       60           1.5                                                  12.5        90           2.0                                           control                                                                              --          5            2.6                                           23      6.25       40           1.7                                                  12.5        70           1.0                                                  25.0        50           1.3                                           control                                                                              --          5            2.6                                           11      6.25       10           2.0                                                  12.5        40           1.8                                                  25.0        40           1.8                                           control                                                                              --          6            3.4                                           25     12.5        0            2.6                                                  25          0            1.1                                                  50          0            1.2                                           control                                                                              --          6            3.4                                           26     12.5        0            2.7                                                  25          0            2.3                                           ______________________________________                                    

The amidine compounds of this invention may be used in the form ofpharmaceutical preparations which contain the compound in associationwith a compatible pharmaceutical carrier. The preparations may be madeup for oral, topical, parenteral, ophthalmic, nasal or rectaladministration, preferably oral. The dosage form may be a solution,suspension, tablet, capsule or other suitable formulation.

It will be apparent to those skilled in the art that many modificationsand changes may be made in the invention described above withoutdeparting from the scope and spirit of the invention.

What is claimed is:
 1. A process for preparing the compound ##STR2##wherein: R₁ is hydrogen, lower alkyl, phenyl, benzyl, or phenyl orbenzyl substituted by lower alkyl, amino, lower alkylamino, nitro,halogen, hydroxy or lower alkoxy;A is CH₂ or CH₂ CH₂ ; R₃ and R₄ areindependently selected from hydrogen, lower alkyl, phenyl or phenylsubstituted with lower alkyl, amino, lower alkylamino, nitro, hydroxy,lower alkoxy or halogen, provided that at least one of R₃ and R₄ isphenyl or substituted phenyl; and R₅ and R₆ are each hydrogen or join toform a double bond at the 2,3-position,and pharmaceutically acceptableaddition salts thereof, which process comprises contacting thecorresponding amidine compound ##STR3## wherein A, R₃, R₄, R₅, and R₆are as described above with about one molar equivalent of R₁ SSR₁ in thepresence of about two molar equivalents of a base and at a temperatureof from about -78° C. to about 0° C., and recovering from the resultantreaction mixture the desired monosulfenylated amidine.
 2. A process forpreparing the compound ##STR4## wherein: R₁ is hydrogen, lower alkyl,phenyl, benzyl, or phenyl or benzyl substituted by lower alkyl, amino,lower alkylamino, nitro, halogen, hydroxy or lower alkoxy;A is CH₂ orCH₂ CH₂ ; R₃ and R₄ are independently selected from hydrogen, loweralkyl, phenyl or phenyl substituted with lower alkyl, amino, loweralkylamino, nitro, hydroxy, lower alkoxy or halogen, provided that atleast one of R₃ and R₄ is phenyl or substituted phenyl; and R₅ and R₆are each hydrogen or join to form a double bond at the 2,3-position,andpharmaceutically acceptable addition salts thereof, which processcomprises contacting the corresponding amidine compound ##STR5## whereinA, R₃, R₄, R₅, and R₆ are as described above with about two molarequivalents of R₁ SSR₁ in the presence of about two molar equivalents ofa base and at a temperature of from about -78° C. to about 23° C., andrecovering from the resultant reaction mixture the desireddisulfenylated amidine.